1. Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.
- Author
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Poon E, Liang T, Jamin Y, Walz S, Kwok C, Hakkert A, Barker K, Urban Z, Thway K, Zeid R, Hallsworth A, Box G, Ebus ME, Licciardello MP, Sbirkov Y, Lazaro G, Calton E, Costa BM, Valenti M, De Haven Brandon A, Webber H, Tardif N, Almeida GS, Christova R, Boysen G, Richards MW, Barone G, Ford A, Bayliss R, Clarke PA, De Bono J, Gray NS, Blagg J, Robinson SP, Eccles SA, Zheleva D, Bradner JE, Molenaar J, Vivanco I, Eilers M, Workman P, Lin CY, and Chesler L
- Subjects
- Adenosine pharmacology, Cell Line, Tumor, Cyclin-Dependent Kinase 2 metabolism, Cyclin-Dependent Kinase 9 metabolism, Enhancer Elements, Genetic, Humans, N-Myc Proto-Oncogene Protein genetics, Neuroblastoma genetics, Neuroblastoma metabolism, Neuroblastoma pathology, Positive Transcriptional Elongation Factor B genetics, Positive Transcriptional Elongation Factor B metabolism, Transcription, Genetic drug effects, Adenosine analogs & derivatives, Cyclin-Dependent Kinase 2 antagonists & inhibitors, Cyclin-Dependent Kinase 9 antagonists & inhibitors, N-Myc Proto-Oncogene Protein biosynthesis, Neuroblastoma drug therapy, Temozolomide pharmacology
- Abstract
The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.
- Published
- 2020
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